Diabetes is a group of diseases whose main symptom is chronic hyperglycemia accompanied by insufficiency of the action of insulin, and involves various characteristic metabolic disorders. The number of patients suffering from diabetes is increasing and, due to changes in lifestyle such as consumption of high-fat diets and lack of exercise, patients suffering from type 2 diabetes, which is a diseased state associated with risk factors such as obesity, hypertriglyceridemia, low HDL cholesteremia, glucose metabolism disorder and/or hypertension and occurs with the metabolic syndrome, are especially increasing. Since it is known that insulin resistance (insufficiency of the action of insulin) is strongly involved in the increase in the number of patients, development of a therapeutic agent for type 2 diabetes having an action that improves insulin resistance has been especially strongly demanded.
Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, which are nuclear receptors, are recently developed therapeutic agents for type 2 diabetes, and known to improve insulin resistance and thereby exert a hypoglycemic action, which is effective for prophylaxis and therapy of diabetes.
As PPAR-γ agonists, only pioglitazone hydrochloride and rosiglitazone maleate are currently commercially available, but agents such as Isaglitazone, Rivoglitazone, Bardoxolone, Aleglitazar, Lobeglitazone, ZYH-1, AVE-0897, Chiglitazar, THR-0921, GFT-505, Indeglitazar, GSK-376501 and Inoglitazone are now being developed and drawing attention as agents effective for therapy of type 2 diabetes.
On the other hand, since PPAR-γ agonists are likely to cause characteristic side effects such as edema and body weight gain, their use is restricted. For example, PPAR-γ agonists cannot be used for patients suffering from heart failure and patients with a history of heart failure, and body weight needs to be appropriately controlled. Since obesity is one of the risk factors for diabetes, body weight gain is a side effect which diabetics want to avoid, so that reduction of the side effects of PPAR-γ agonists has been strongly demanded.
In view of this, a method has been disclosed in which a highly safe and effective therapeutic effect for diabetes is exhibited by using a PPAR-γ agonist in combination with another therapeutic agent or prophylactic agent for diabetes having a different action mechanism (e.g., α-glycosidase inhibitor, sulfonylurea agent, biguanide, aldose reductase inhibitor, statin compound, squalene synthesis inhibitor, fibrate compound, LDL catabolism promoter or angiotensin converting enzyme inhibitor) (JP 2007-191494 A).
It has been disclosed that an IP agonist such as a prostaglandin I2 derivative has the actions of vasodilation, platelet aggregation inhibition, smooth-muscle proliferation inhibition, vascular endothelium protection and inflammatory cytokine inhibition and is effective as a therapeutic agent for diabetes in cases where it is used alone (JP 2-167227 A, Paolisso et al., Diabetes Care, 18, 200-205, 1995), and that an IP agonist is effective for therapy or prophylaxis of diabetes when combined with a PPAR-γ agonist (JP 2006-199694 A). However, in JP '694, the PPAR-γ agonist is merely listed as one of many arbitrary components and there is no particular description suggesting or supporting a combined effect with an IP agonist. Further, the fact that cicletanine, which is known as an endogenous prostacyclin inducer, exerts a synergistic therapeutic effect for diabetes when used in combination with a PPAR-γ agonist (Japanese Translated PCT Patent Application Laid-open No. 2006-523668), and expected matters on lipid metabolism, control of edema and reduction of hepatotoxicity of PPAR-γ agonists are described (WO 2006/034510). However, these reports do not describe that an IP agonist suppresses body weight gain due to a PPAR-γ agonist.
An IP agonist beraprost sodium has been widely employed as an orally-available stable prostaglandin I2 derivative for basic research and clinical applications, to be used as a therapeutic agent for chronic artery obstruction (Melian et al., Drugs, 62, 107-133, 2002) or primary pulmonary hypertension (Hashida et al., Angiology, 49, 161-164, 1998 and Miyata et al., J. Cardiovasc. Pharmacol., 27, 20-26, 1996). Since beraprost sodium and its derivatives have a platelet aggregation inhibition action, they are suggested as having possibilities to be useful as antithrombotic agents, and also reported to have an anti-hyperlipemic action (JP 1-53672 B and JP 62-286924 A). Further, it has been discovered that beraprost sodium is effective for diabetic complications such as arterial sclerosis, diabetic nephropathy, diabetic microangiopathy, diabetic neuropathy, diabetic retinopathy and diabetic macroangiopathy (WO 99/13880), and that the combination of beraprost sodium and an antidiabetic drug enables amelioration of decrease in the functions of the motor nerve and the sensory nerve, which have not been able to be sufficiently treated with conventional antidiabetic drugs, by improvement of the nerve conduction velocity. In view of this, a therapeutic method for diabetic neuropathy using the combination of these drugs is disclosed (JP 10-251146 A). However, the target diseases are different in these reports, and the reports do not describe a therapeutic effect for diabetes by the combination of beraprost sodium and an antidiabetic drug. Further, it is disclosed that beraprost sodium is effective for therapy or prophylaxis of diabetes when it is used in combination with pioglitazone hydrochloride (JP '694), but beraprost sodium and pioglitazone hydrochloride are merely listed as one of many combinations of IP agonist drugs and PPAR-γ agonist drugs, and there is no particular description suggesting or supporting the combined effect.
However, it has not been known so far that IP agonists can be therapeutic agents or prophylactic agents which not only suppress the side effect of PPAR-γ agonists, that is, the body weight-increasing action, but also have an excellent hypoglycemic action
It could therefore be helpful to provide a therapeutic or prophylactic agent for diabetes comprising as an effective component a PPAR-γ agonist, which agent exhibits a reduced side effect of the PPAR-γ agonist.